Senior author Harvey Cantor, MD
A new focus on the immune system's ability to both unleash and
restrain its attack on disease has led Dana-Farber Cancer Institute
scientists to identify cells in mice that prevent the immune system from
attacking the animals' own cells, protecting them from autoimmune
diseases such as multiple sclerosis, type 1 diabetes, and lupus.
The discovery, reported online on Sept. 16 by the journal Nature,
may give scientists an effective way of operating the immune system's
internal "control panel," leading to improved therapies for a variety of
diseases — from vaccines that prompt the immune system to stage a
sustained assault on cancers, to treatments that derail the biological
onslaught associated with autoimmune diseases. The fact that human
immune system cells share key features with those in mice makes the
prospect of such advances quite realistic, the study authors say.
"The traditional view of the immune system is of specialized groups
of cells poised to attack foreign pathogens [disease-causing agents],"
says senior author Harvey Cantor, MD,
who is the chair of the Department of Cancer Immunology and AIDS at
Dana-Farber. "While that model is generally correct, we've come to
appreciate that the immune system, like other complex biological
information systems, includes a counterbalance mechanism — a set of
cells programmed to suppress the immune response. Such cells are
essential to preventing excessive reactions to pathogens and misguided
attacks on the body's own cells."
The search for cells involved in quieting the immune response has
previously focused on immune system cells known as CD4+ T cells, some of
which have been shown to prevent abnormal inflammation in response to
disease or infection. In the new study, lead author Hye-Jung Kim, PhD,
and her colleagues found that CD8+ T cells (known as killer T cells
because of their ability to kill diseased cells) also include a subset
that helps dampen the immune response. Instead of reducing inflammation
like their CD4 cousins, the CD8+ T regulatory (CD8+Treg) cells ensure
that the immune system doesn't produce antibodies that attack normal
The Dana-Farber team discovered how CD8+ Treg accomplish this feat.
They mingle with cells known as follicular T-helper cells, which are
intermediaries that prompt the immune system's B cells to make
disease-fighting antibodies. The meeting with CD8+ Treg cells
essentially shuts off the follicular T-helper cells, preventing them
from interacting with B cells. No interaction means no production of
antibodies, which means no assault on an animal's normal, healthy cells.
The critical point of contact between CD8+ Treg cells and follicular
T-helper cells is a protein on the helper cells called Qa-1. When Kim
and her colleagues bred a strain of mouse with abnormal Qa-1, the
animals developed a form of lupus. The reason: the CD8+ Treg cells
couldn't latch onto the defective protein, leaving the follicular cells
free to order the B cells to produce antibodies, some of which targeted
the animals' own tissue.
The significance of this work is that CD8+ Treg cells represent a new
lever for raising or lowering the strength of the immune response.
This class of cells, it turns out, depends for its survival on a
cytokine (a regulatory compound) called interleukin 15. Increase the
supply of CD8+ Treg cells and the immune response is suppressed — a
potentially powerful way of dealing with autoimmune diseases. Decrease
the amount of such cells and the immune response can be invigorated and
extended — a useful complement to vaccines that unleash the immune
system on cancer.
"Experience has shown that vaccines that simply activate or expand
the number of T and B cells are not likely to result in a prolonged,
robust anti-tumor response," Cantor explains. "The balancing mechanism
within the immune system means that when more disease-fighting cells are
generated, there's a countervailing increase in the number of
immune-suppressing cells that are generated. The key is to break that
loop. This work brings that goal closer."
Co-authors of the study include Bert Verbinnen, PhD, and Xiaolei
Tang, MD, PhD, of Dana-Farber, and Linrong Lu, PhD, currently of
Zhejiang University in Hangzhou, China.
The research was supported by grants from the National Institutes of
Health, the Lupus Research Institute, and the Schecter Research